Risk Of Early Disease Progression Research Articles

Development of Biomarkers and Prognosis Model of Mortality Risk in Patients with COVID-19.

As of 30 April 2023, the COVID-19 pandemic has resulted in over 6.9 million deaths worldwide. The virus continues to spread and mutate, leading to continuously evolving pathological and physiological processes. It is imperative to reevaluate predictive factors for identifying the risk of early disease progression. A retrospective study was conducted on a cohort of 1379 COVID-19 patients who were discharged from Xin Hua Hospital affiliated with Shanghai Jiao Tong University School of Medicine between 15 December 2022 and 15 February 2023. Patient symptoms, comorbidities, demographics, vital signs, and laboratory test results were systematically documented. The dataset was split into testing and training sets, and 15 different machine learning algorithms were employed to construct prediction models. These models were assessed for accuracy and area under the receiver operating characteristic curve (AUROC), and the best-performing model was selected for further analysis. AUROC for models generated by 15 machine learning algorithms all exceeded 90%, and the accuracy of 10 of them also surpassed 90%. Light Gradient Boosting model emerged as the optimal choice, with accuracy of 0.928 ± 0.0006 and an AUROC of 0.976 ± 0.0028. Notably, the factors with the greatest impact on in-hospital mortality were growth stimulation expressed gene 2 (ST2,19.3%), interleukin-8 (IL-8,17.2%), interleukin-6 (IL-6,6.4%), age (6.1%), NT-proBNP (5.1%), interleukin-2 receptor (IL-2R, 5%), troponin I (TNI,4.6%), congestive heart failure (3.3%) in Light Gradient Boosting model. ST-2, IL-8, IL-6, NT-proBNP, IL-2R, TNI, age and congestive heart failure were significant predictors of in-hospital mortality among COVID-19 patients.

Algorithme thérapeutique des CBNPC sans mutation addictive: Algorithm of NSCLC management outside oncogenic addiction

The development of immunotherapy in first-line therapy with anti-PD-1 and anti-PD-L1 has changed the first line treatment algorithm of advanced NSCLC. The anti-PD-(L)1 pembrolizumab, atézolizumab and cemiplimab clearly improve the overall survival in NSCLC with high PD-L1 expression (≥ 50% of tumour cells), comparatively to cytotoxic chemotherapy. Combinations of anti-PD(L)-1 to platinum-based chemotherapy are superior to chemotherapy alone, regardless of PD-L1 level of expression. They represent the 1st line gold-standard when PD-L1 is expressed in less than 50 % of tumour cells and might reduce the risk of early disease progression in comparison with pembrolizumab when PD-L1 ≥ 50%. The room for anti-CTLA-4 + anti-PD(L)-1 combinations which are not available in France remains to be established. Second-line treatment is currently based on chemotherapy, with a platinum-based doublet for patients treated in first line by pembrolizumab alone, and standard second-line chemotherapy options for patients treated by chemotherapy-immunotherapy combinations, i.e. docétaxel regardless of histology or pemetrexed for non-squamous cell carcinoma when not used in first line. Addition of an antiangiogenic agent to docetaxel only achieved a modest improvement of overall survival but neither nintedanib, nor docetaxel is available in France. Combination of paclitaxel and bevacizumab is also an option. Immunotherapy still benefits only a minority of patients whose identification is imperfect, underscoring the need for new strategies based on ne‹ combination amplifying the anti-tumour immune response as well as understanding the mechanisms of resistance to treatment in order to improve these results. Supportive care remains crucial for all patients from the time of diagnosis.1877-1203/© 2023 SPLF. Published by Elsevier Masson SAS. All rights reserved.

The TT Genotype of the KIAA1524 rs2278911 Polymorphism Is Associated with Poor Prognosis in Multiple Myeloma

The KIAA1524 gene encodes an oncoprotein, CIP2A, which inhibits the phosphorylation of the Akt kinase B, stabilizes the c-Myc protein, and, through that, promotes cancerogenesis. An increase in CIP2A expression has been observed in numerous solid tumors and hematologic malignancies, including multiple myeloma (MM). The aim of our study was to evaluate the clinical impact of the functional single nucleotide polymorphisms (SNP) of the KIAA1524 gene (rs2278911, 686C > T) in MM patients. The study group consisted of 128 patients with de novo MM. EDTA venous blood samples were collected prior to the treatment. The SNPs were analyzed by Real-Time PCR with the use of specific Taqman probes. Multivariable analysis revealed that variables independently associated with shorter progression-free survival (PFS) included thrombocytopenia, delTP53 and IGH/CCND1 translocation and the TT genotype of the KIAA1524 gene (686C > T) (median PFS: 6 vs. 25 months; HR = 7.18). On the other hand, autologous haematopoietic stem cell transplantation (AHSCT) was related to a lower risk of early disease progression. Moreover, light chain disease, International Staging System (ISS) 3, poor performance status, hypoalbuminemia, IGH/FGFR3 translocation and the TT genotype of the KIAA1524 gene (686C > T) were independent prognostic factors associated with shorter overall survival (OS) (median OS: 8 vs. 45 months; HR = 7.08). The evaluation of the SNP 686C > T of the KIAA1524 gene could be used as a diagnostic tool in MM patients at risk of early disease progression and death.

Algorithme thérapeutique des CBNPC sans mutation addictive

The development of immunotherapy in first-line therapy with anti-PD-1 and anti-PD-L1 has changed the first line treatment algorithm of advanced NSCLC. The anti-PD-1 pembrolizumab and cemiplimab clearly improve the overall survival in NSCLC with high PD-L1 expression (≥ 50% of tumour cells), comparatively to cytotoxic chemotherapy. Combinations of anti-PD(L)-1 to platinum-based chemotherapy are superior to chemotherapy alone, independently of PD-L1 level of expression. They represent the 1st line gold-standard when PD-L1 is expressed in less than 50% of tumour cells and might reduce the risk of early disease progression in comparison with pembrolizumab when PD-L1 ≥ 50%. The room for anti-CTLA-4 + anti-PD(L)-1 combinations which are not available in France remains to be established. Second-line treatment is currently based on chemotherapy, with a platinum-based doublet for patients treated in first line by pembrolizumab alone, and standard second-line chemotherapy options for patients treated by chemotherapy-immunotherapy combinations, i.e. docétaxel regardless of histology or pemetrexed for non-squamous cell carcinoma when not used in first line. Addition of an antiangiogenic agent to docetaxel only achieved a modest improvement of overall survival but neither nintedanib, nor docetaxel is available in France. Immunotherapy still benefits only a minority of patients whose identification is imperfect, underscoring the need for new strategies based on characterizing, initiating, and amplifying the antitumour immune response as well as understanding the mechanisms of resistance to treatment in order to improve these results.1877-1203/© 2022 SPLF. Published by Elsevier Masson SAS. All rights reserved.

PARP Inhibitors: A Major Therapeutic Option in Endocrine-Receptor Positive Breast Cancers.

Simple SummaryOlympiAD and EMBRACA trials demonstrated the efficacy of PARPi, compared to chemotherapy, in patients with HER2-negative metastatic breast cancers (mBC) carrying a germline BRCA mutation. Patients with ER+/HER2-BRCA-mutated mBC seemed to have a higher risk of early disease progression while on CDK4/6 inhibitors and benefit from PARPi, especially when prescribed before chemotherapy. Importantly, the frequency of BRCA pathogenic variant (PV) carriers among ER+/HER2- breast cancer patients has been underestimated, and 50% of all BRCA1/2 mutated breast cancers are actually of ER+/HER2- subtype. Recent studies also highlight the benefit of PARPi in BRCA wild type mBC with HRD representing up to 20% of ER+/HER2- breast cancers. The OLYMPIA trial also demonstrated PARPi utility in patients with ER+/HER2- early breast cancers with BRCA PV at high risk of relapse. Consequently, implementation of early genotyping and new strategies for identifying patients with high-risk ER+/HER2- HRD breast cancers likely to benefit from PARPi is of high importance.Recently, OlympiAD and EMBRACA trials demonstrated the favorable efficacy/toxicity ratio of PARPi, compared to chemotherapy, in patients with HER2-negative metastatic breast cancers (mBC) carrying a germline BRCA mutation. PARPi have been largely adopted in triple-negative metastatic breast cancer, but their place has been less clearly defined in endocrine-receptor positive, HER2 negative (ER+/ HER2-) mBC. The present narrative review aims at addressing this question by identifying the patients that are more likely benefit from PARPi. Frequencies of BRCA pathogenic variant (PV) carriers among ER+/HER2- breast cancer patients have been underestimated, and many experts assume than 50% of all BRCA1/2 mutated breast cancers are of ER+/HER2- subtype. Patients with ER+/HER2- BRCA-mutated mBC seemed to have a higher risk of early disease progression while on CDK4/6 inhibitors and PARPi are effective especially when prescribed before exposure to chemotherapy. The OLYMPIA trial also highlighted the utility of PARPi in patients with early breast cancers at high risk of relapse and carrying PV of BRCA. PARPi might also be effective in patients with HRD diseases, representing up to 20% of ER+/HER2- breast cancers. Consequently, the future implementation of early genotyping strategies for identifying the patients with high-risk ER+/HER2- HRD breast cancers likely to benefit from PARPi is of high importance.

Real-world benefit of combination palbociclib and endocrine therapy for metastatic breast cancer and correlation with neutropenia.

BackgroundCombination CDK4/6 inhibitor and endocrine therapy has been shown to significantly improve progression‐free survival (PFS) in patients with hormone receptor (HR)‐positive, HER2‐negative metastatic breast cancer (mBC). The aim of this retrospective study was to evaluate the real‐world benefit of first‐line combination therapy in this cohort and to correlate treatment efficacy with neutropenia, a common toxicity of CDK4/6 inhibitors.MethodsThis study included HR‐positive, HER2‐negative advanced or mBC patients who were treated with palbociclib plus endocrine therapy, mainly letrozole, between 1 January 2015 and 1 March 2018. Progression‐free survival (PFS) was determined using Kaplan–Meier analysis. The predictive value of absolute neutrophil count (ANC) and neutrophil‐to‐lymphocyte ratio (NLR) for PFS were explored using Cox regression models. Both ANC and NLR were used as a time‐dependent variable.ResultsIn total, 165 patients were included with median PFS of 24.19 months (95% CI 18.93–NR). Median PFS for patients with bone‐only metastases (n = 54) was not reached (95% CI 18.21–NR). Among patients with all other metastases (n = 111), median PFS was 24.19 months (95% CI 16.33–33.82). Lower ANC was correlated with decreased risk of progression (HR 0.84, 95% CI 0.71–0.97, p = 0.008). There was no significant association between NLR and the risk of disease progression (HR 1.07, 95% CI 0.97–1.18, p = 0.203).ConclusionThe effectiveness of palbociclib and endocrine therapy in the treatment of HR‐positive, HER2‐negative mBC in the real‐world setting is similar to the efficacy reported in the PALOMA‐2 trial. Patients with lower neutrophil count may have a lower risk of early disease progression.

Algorithme thérapeutique des CBNPC sans anomalie moléculaire actionnable: Therapeutic algorithm for NSCLC without actionable molecular abnormalities

The development of immunotherapy in first-line therapy with anti-PD-1 and anti-PD-L1 has changed the first line treatment algorithm of advanced NSCLC. The anti-PD-1 pembrolizumab and cemiplimab clearly improve the overall survival in NSCLC with high PD-L1 expression (≥ 50% of tumour cells), comparatively to cytotoxic chemotherapy. Combinations of anti-PD(L)-1 to platinum-based chemotherapy are superior to chemotherapy alone, independently of PD-L1 level of expression. They represent the 1st line gold-standard when PD-L1 is expressed in less than 50% of tumour cells and might reduce the risk of early disease progression in comparison with pembrolizumab when PD-L1 ≥50%. The room for anti-CTLA-4 + anti-PD(L)-1 combinations which are not available in France remains to be established. Second-line treatment is currently based on chemotherapy, with a platinum-based doublet for patients treated in first line by pembrolizumab alone, and standard second-line chemotherapy options for patients treated by chemotherapy-immunotherapy combinations, i.e. docétaxel regardless of histology or pemetrexed for non-squamous cell carcinoma when not used in first line. Addition of an antiangiogenic agent to docetaxel only achieved a modest improvement of overall survival but neither nintedanib nor ramucirumab are available in France. Immunotherapy still benefits only a minority of patients whose identification is imperfect, underscoring the need for new strategies based on characterizing, initiating, and amplifying the anti-tumour immune response as well as understanding the mechanisms of resistance to treatment in order to improve these results.© 2021 SPLF. Published by Elsevier Masson SAS. All rights reserved.

High-risk myeloma: a challenge to define and to determine the optimal treatment

Biomarkers that can identify patients with multiple myeloma at high risk of early disease progression and death are now well established. These biomarkers include molecular lesions, such as the clonal initiating translocations t(4;14), t(14;16), and t(14;20), copy number abnormalities, such as gain(1q) and del(17p), somatic mutations, and gene expression signatures. Other pathological or physiological features can also contribute, such as plasma cell leukaemia and renal failure. Unfortunately, despite substantial progress in therapeutics for patients with myeloma in the past decade, outcomes for patients with high-risk myeloma remain poor.

Première ligne des CBNPC avancés sans addiction oncogénique : quel traitement pour quel patient ?: Frontline treatment of advanced NSCLC without oncogenic addiction: which treatment for which patient?

The development of immunotherapy in first-line therapy of advanced NSCLC has changed the treatment algorithm which revolves around the blockade of PD-1 - PD-L1 axis. The anti-PD-1 pembrolizumab clearly improves the overall survival in NSCLC with PD-L1 expression in greater than 50% of tumour cells, comparatively to cytotoxic chemotherapy. Combinations of anti-PD(L)-1 to platinum-based chemotherapy are superior to chemotherapy alone, independently of PD-L1 level of expression. They represent the 1st line gold-standard when PD-L1 is expressed in less than 50% of tumour cells and reduce the risk of early disease progression in comparison with pembrolizumab as a single agent when PD-L1 ≥50%, without evidence of an impact on long term survival. The room for ipilimumab-nivolumab in combination with two courses of induction chemotherapy remains to be established. Ipilimumab might increase the proportion of patients deriving a long term benefit from immunotherapy in case of PD-L1 negative or low tumours. Today, making a treatment decision in clinical practice remains based upon PD-L1 level of expression and patient clinical profile, especially in terms of tumour burden and aggressiveness.© 2020 SPLF. Published by Elsevier Masson SAS. All rights reserved.

Traitements systémiques de première ligne dans les CBNPC avancés en l’absence d’addiction oncogénique: Frontline systemic treatment of advanced NSCLC without oncogenic addiction

AbstractFirst-line treatment of metastatic NSCLC without oncogenic addiction was based on chemotherapy regimen combining a platinum salt and a third generation cytotoxic drug, with similar results for the different available schedules. The improvement of chemotherapy results has been limited to non-squamous carcinoma, deriving from maintenance strategies mainly based on continuation of pemetrexed as a single agent and on addition of bevacizumab to chemotherapy. The development of immunotherapy in first-line therapy with anti-PD-1 and anti-PD-L1 has changed the first line treatment algorithm of advanced NSCLC. The anti-PD-1 pembrolizumab clearly improves the overall survival in NSCLC with PD-L1 expression in greater than 50% of tumour cells, comparatively to cytotoxic chemotherapy. Combinations of anti-PD(L)-1 to platinum-based chemotherapy are superior to chemotherapy alone, independently of PD-L1 level of expression. They represent the 1st line gold-standard when PD-L1 is expressed in less than 50% of tumour cells and might reduce the risk of early disease progression in comparison with pembrolizumab when PD-L1 ≥50%. The room for anti-CTLA-4 + anti-PD(L)-1 combinations remains to be established.© 2020 SPLF. Published by Elsevier Masson SAS. All rights reserved.

Rationale and design of a longitudinal study of cerebral small vessel diseases, clinical and imaging outcomes in patients presenting with mild ischaemic stroke: Mild Stroke Study 3.

BackgroundCerebral small vessel disease is a major cause of dementia and stroke, visible on brain magnetic resonance imaging. Recent data suggest that small vessel disease lesions may be dynamic, damage extends into normal-appearing brain and microvascular dysfunctions include abnormal blood–brain barrier leakage, vasoreactivity and pulsatility, but much remains unknown regarding underlying pathophysiology, symptoms, clinical features and risk factors of small vessel disease.Patients and Methods: The Mild Stroke Study 3 is a prospective observational cohort study to identify risk factors for and clinical implications of small vessel disease progression and regression among up to 300 adults with non-disabling stroke. We perform detailed serial clinical, cognitive, lifestyle, physiological, retinal and brain magnetic resonance imaging assessments over one year; we assess cerebrovascular reactivity, blood flow, pulsatility and blood–brain barrier leakage on magnetic resonance imaging at baseline; we follow up to four years by post and phone. The study is registered ISRCTN 12113543.SummaryFactors which influence direction and rate of change of small vessel disease lesions are poorly understood. We investigate the role of small vessel dysfunction using advanced serial neuroimaging in a deeply phenotyped cohort to increase understanding of the natural history of small vessel disease, identify those at highest risk of early disease progression or regression and uncover novel targets for small vessel disease prevention and therapy.

Abstract P2-17-03: Real-world benefit of CDK4/6 inhibitor and endocrine therapy combination in metastatic breast cancer and correlation with neutropenia

Abstract Background: Combination of a CDK4/6 inhibitor plus endocrine therapy has been shown to significantly improve the progression free survival (PFS) in patients with hormone-receptor (HR)+, HER2- metastatic breast cancer. The aims of this retrospective study was: 1) to evaluate the real-world benefit of palbociclib plus endocrine therapy as the first line treatment in HR+, HER2- metastatic breast cancer (mBC) and 2) to correlate efficacy of the combination with neutropenia (which is a common toxicity of CDK4/6 inhibitors). Methods: This study included HR+, HER2- advanced mBC patients who were treated with palbociclib plus an endocrine therapy (mainly letrozole) at Moffitt Cancer Center between January 1, 2015 and March 1, 2018. The PFS was determined using Kaplan-Meier analysis. The predictive value of absolute neutrophil count (ANC) and neutrophil-to-lymphocyte ratio (NLR) for PFS were investigated using the univariable and multivariable Cox models. Results: A total of 165 patients were included in this retrospective cohort study. The median PFS of the full cohort was 24.19 months (95% CI 18.93 to not reached). For patients with bone metastasis only (n = 54), the median PFS was not reached (95% CI 18.21 to not reached). For patients with non-bone-only metastasis (n = 111), the median PFS was 24.19 months (95% CI 16.33 to 33.82). Patients with higher absolute neutrophil counts (ANC) are at high risk of disease progression (HR 1.15; 95% CI 1.03 to 1.29, p = 0.013). We did not find a significant association between the value of NLR and the risk of disease progression (HR 1.07 95% 0.97 to 1.18, p = 0.203). Both ANC and NLR were used as a time dependent variable. Conclusion:The effectiveness of palbociclib plus letrozole in the treatment of HR+, HER2- metastatic breast cancer in the real-world setting was found to be similar to the results from the PALOMA-2 trial. In addition, patients with a higher ANC were found to have a higher risk for early disease progression. This has implication for clinical practice [i.e., frequent dose delay and/or dose reduction based on ANC threshold of 1000/uL may not be an optimal approach. Since infection is rare, it is reasonable to reduce this threshold to a lower level such as 750-800/uL]. Citation Format: Dakota Jenneman, Xiaojun Zhong, Junjie Ma, Weihong Sun, Heather Han, Hatem Soliman, Loretta Loftus, Ricardo Costa, Avan Armaghani, Aixa Soyano, Brian Czerniecki, M. Catherine Lee, John Kiluk, Nazanin Khakpour, Susan Hoover, Christine Laronga, Hung T Khong. Real-world benefit of CDK4/6 inhibitor and endocrine therapy combination in metastatic breast cancer and correlation with neutropenia [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-17-03.

769P - Prognosis of esophageal squamous cell carcinoma based on local immunity evaluation

BackgroundThe purpose of the study was to assess the significance of the local cytokine composition in patients with esophageal squamous cell carcinoma (EC) for the disease prognosis. MethodsCytokines were studied in tumor, peritumoral (PT) and resection line (RL) tissues of 36 patients with stage II-III EC. All patients received surgery; further treatment depended on the tumor stage. During the observation, patients were divided into groups with short and prolonged progression-free survival (< and >1.5 years). Levels of TNF-α, IL-1b, IL-6, IL-8, and IL-10 were determined in tissue homogenates by ELISA and calculated in pg/mL/g of protein. Discriminant and ROC analyses were performed with the calculation of the area under a ROC curve (AUC) and cut-off points for statistically significant indicators sharing with maximum diagnostic sensitivity (DSe) and specificity (DSp) two alternative signs: the presence or absence of the risk of early progression. ResultsPatients showed different initial levels of tissue pro-and anti-inflammatory cytokines. PT of patients with the further progression was characterized by higher levels of TNF-α (by 1.9) and IL-10 (by 1.6 times), and their tumor tissues – by 2.1 times higher IL-1b and 1.6 times higher IL-8 (p<0.05). The ROC analysis demonstrated the following cut-off values: in tumors 57.5pg/mL/g (IL-1b) and 4.5pg/mL/g (IL-10), in PT 36.0pg/mL/g (IL-8) and 7.4pg/mL/g (TNF-α), in RL 9.8pg/mL/g (TNF-α) and 5.2pg/mL/g (IL-10). Exceeding them involved the risk of early disease progression. Levels of TNF-α in PT, IL-10 in tumors and RL showed good (AUC 0.8-0.9), and levels of TNF-α in RL, IL-1b in tumors and IL-8 in PT - satisfactory (AUC 0.7-0.8) ability to recognize the risk of early EC progression, p<0.005. ConclusionsEvaluation of local levels of cytokines allowed identifying the risk criteria for the development of early progression of EC, which along with clinical signs (the process spread) determine its prognosis. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Progression of Colorectal Liver Metastases from the End of Chemotherapy to Resection: A New Contraindication to Surgery?

Not all patients with resectable colorectal liver metastases (CLM) benefit from liver resection (LR); only patients with disease progression during chemotherapy are excluded from surgery. This study was performed to determine whether tumor behavior (stable disease/progression) from the end of chemotherapy to LR impacts prognosis. Patients undergoing LR after tumor response or stabilization during chemotherapy were considered. Overall, 128 patients who underwent examination by two imaging modalities (computed tomography/magnetic resonance imaging) after chemotherapy with a>3-week interval between the two imaging modalities were analyzed. Any variation in CLM size was registered. Tumor progression was defined according to the response evaluation criteria in solid tumors (RECIST) criteria. Among 128 patients with stable disease or partial response to preoperative chemotherapy, 32 (25%) developed disease progression in the chemotherapy to LR interval, with a disease progression rate of 17% when this interval was<8weeks. Survival was lower among patients with progression than those with stable disease [3-year overall survival (OS) 23.0 vs. 52.4%, and recurrence-free survival (RFS) 6.3% vs. 21.6%; p<0.001]. Survival was extremely poor in patients with early progression (<8weeks) (0.0% 2-year OS, 12.5% 6-month RFS). Disease progression in the chemotherapy to LR interval was an independent negative prognostic factor for OS and RFS [hazard ratio 3.144 and 2.350, respectively; p<0.001]. Early disease progression in the chemotherapy to LR interval occurred in approximately 15% of patients and was associated with extremely poor survival. Even if these data require validation, the risk for early disease progression after chemotherapy should be considered, and, if progression is evident, the indication for surgery should be cautiously evaluated.

Pancreatic neuroendocrine tumor: Correlations between MRI features, tumor biology, and clinical outcome after surgery.

To assess which magnetic resonance imaging (MRI) features are associated with pNETs (pancreatic neuroendocrine tumors) grade based on the WHO classification, as well as identify MRI features related to disease progression after surgery. In this Institutional Review Board (IRB)-approved study, 1.5T and 3.0T MRI scans of 80 patients with surgically verified pNETs were assessed. The images were evaluated for tumor location; size; pattern; predominant signal intensity on precontrast T1 - and T2 -weighted images, as well as on postcontrast arterial and portal venous phase T1 -weighted sequences; presence of pancreatic duct dilatation; pancreatic atrophy; restricted diffusion; vascular involvement by the tumor; extrapancreatic tumor spread; and synchronous liver metastases. Tumors were graded based on the WHO classification and patients were followed-up with computed tomography (CT) or MRI after surgical resection. Data were analyzed with Student's t and chi-square tests, logistic regression, and Kaplan-Meier curves. The MRI features that were associated with aggressive tumors were: size >2.0 cm (odds ratio [OR] = 4.8, P = 0.002), "T2 nonbright lesions" on T2 -weighted images (OR = 4.6, P = 0.008), presence of pancreatic ductal dilatation (OR = 4.9, P = 0.024), and restricted diffusion within the lesion (OR = 4.9, P = 0.013). Differences in progression-free survival distribution were found for patients whose pNETs were associated with the following MRI features: size >2.0 cm (χ2 (1) = 6.0, P = 0.014), "nonbright lesions" on T2 -weighted images (χ2 (1) = 6.8, P = 0.009), and presence of pancreatic duct dilatation (χ2 (1) = 10.9, P = 0.001). MRI features can be used to assess pNETs aggressiveness and identify patients at risk for early disease progression after surgical resection. 3 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:425-432.

A Phase 2 Study of Lenalidomide to Repair Immune Synapse Response and Humoral Immunity in Early-Stage, Asymptomatic Chronic Llmphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) with High-Risk Genomic Features

BACKGROUND: Patients (pts) with CLL/SLL are at high risk for infections, and pts with genetically high-risk disease are at increased risk for early disease progression and death. Lenalidomide, an oral immunomodulatory agent with demonstrated activity in treatment-naïve CLL/SLL, can potentially restore immune system dysfunction associated with CLL/SLL. We present results from an NCI/CTEP-sponsored, randomized phase 2 study (NCI 8834) of low-dose lenalidomide designed to assess the ability of lenalidomide to restore immune synapse response and humoral immunity, as well as delay progression of asymptomatic, genetically high-risk, early-stage CLL/SLL.METHODS: Pts with genetically high-risk CLL/SLL (unmutated IGHV, deletion(17p)/(11q), and/or complex abnormal karyotype) were eligible if they were treatment-naïve, did not meet IWCLL 2008 criteria for initiating therapy, age ≥ 18 but < 80 years, ECOG ≤ 2, no history of autoimmune cytopenia, no venous thromboembolic event ≤6 months prior, and adequate end-organ function. Pts were randomized to receive lenalidomide either concurrent with (Arm A) or sequential to (Arm B) 2 doses of 13-valent protein-conjugated pneumococcal vaccine (Prevnar-13) administered 2 months apart (see figure). Lenalidomide was dosed at 2.5 mg/day during the first 28-day cycle to reduce risk for tumor flare and increased to 5 mg/day for the second and subsequent cycles as tolerated. Treatment continued for at least 24 cycles in the absence of disease progression or irreversible Grade ≥ 3 adverse event (AE). Anti-pneumococcal antibody titers, the primary endpoint of the study, were measured in each arm at 1 and 2 months after the second dose of vaccine and every 6 months thereafter. Secondary endpoints included clinical response, IWCLL 2008 response after 24 cycles, and progression-free survival (PFS).RESULTS: 49 pts were randomized. Median age at enrollment was 59 (range 40-70) years, median time from diagnosis 1.26 (range 0.15-9) years, and ECOG = 0 in 96%. Baseline clinical and genetic risk factors were similar between the 2 arms (see table). In general, AE were mild and manageable. Gr ≥3 AE were uncommon and included (in ≥10% pts): neutropenia in 10 (20%) and hypophosphatemia in 6 (12%). The most common treatment-emergent Gr 1/2 AEs included neutropenia in 27 pts (55%), diarrhea in 26 (53%), rash in 25 (51%), and thrombocytopenia in 23 (47%). Gr 1/2 infections were reported in 17 (35%), but only 1 Gr 3 infection (pneumonia) was observed. Gr 1/2 tumor flare was observed in 2 pts (4%). There were no thromboembolic events. Seroprotection against 7 pneumococcal serotypes (1, 3, 4, 5, 14, 19F, and 23F) was measured 4 weeks after the second dose of vaccine. All but 4 pts (3 in Arm A, 1 in Arm B) achieved seroprotection against ≥1 serotype, and the median number against which seroprotection was achieved was 3 (range: 0-7) in both arms. Mean IgG/IgM/IgA levels at baseline were 722/109/49, and improved to 820/136/51 and 947/197/59 after 12 and 24 cycles of treatment, respectively. Disposition of study patients and treatment responses are summarized in the table; after median 31 cycles received, 59% of patients remain on treatment. 75% of patients achieved a clinically assessed disease response, and of the 34 patients that completed IWCLL response assessment after 24 cycles of therapy (including CT scans and bone marrow biopsy), 9 achieved a PR, 23 SD, and 2 PD. Median PFS has not yet been reached; 1 year PFS was 88% (95%CI 74-94), 2 year PFS was 78% (63-88), and estimated 3 year is PFS 72% (95%CI 56-83).CONCLUSIONS: Low-dose lenalidomide can be administered to asymptomatic, genetically high-risk, early-stage CLL patients with modest toxicity and high rates of durable clinical response. Some anti-pneumococcal vaccine response was achieved by nearly all treated patients on both schedules. Lenalidomide effectively prevented and/or reversed the expected progression of hypogammaglublinemia, which may explain the low incidence of infection, and near absence of severe infection, observed here. [Display omitted] [Display omitted] DisclosuresJones:Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding. Awan:Novartis Oncology: Consultancy; Innate Pharma: Research Funding; Pharmacyclics: Consultancy. Andritsos:Hairy Cell Leukemia Foundation: Research Funding. Woyach:Morphosys: Research Funding; Karyopharm: Research Funding; Acerta: Research Funding. Lozanski:Stemline Therapeutics Inc.: Research Funding; Genentech: Research Funding; Beckman Coulter: Research Funding; Boehringer Ingelheim: Research Funding.

Histiocytose Langerhansienne pulmonaire de l’adulte

There is a strong relationship between tobacco smoking and pulmonary Langerhans cell histiocytosis (LCH) in adults. Definitive diagnosis relies on lung histology. In certain cases, the diagnosis can be retained on a typical nodulo-cystic pattern on lung high-resolution computed tomography (HRCT) and appropriate clinical setting. The main differential diagnoses to consider vary according to nodulo-cystic or only cystic pattern on lung HRCT and the clinical context. The natural history of the disease is better known and regular evaluation of respiratory function is essential during the follow-up of the patients. The disease may regress or remain stable and mild without treatment in a significant number of cases. Smoking cessation is the essential first step because it reduces the risk of early disease progression. Cladribine is the only treatment that has shown improvement in respiratory function. Its efficacy and tolerance will be clarified in the near future. Therapies targeting mutations in the MAPK pathway represent new therapeutic options that need to be appropriately evaluated pulmonary LCH.

MicroRNA Expression in a Readily Accessible Common Hepatic Artery Lymph Node Predicts Time to Pancreatic Cancer Recurrence Postresection

Lymph node involvement in pancreatic adenocarcinoma (PAC) predicts postresection survival, but early lymph node metastasis detection is not easily accomplished. We assessed a panel of microRNAs (miRNAs) in a common hepatic artery lymph node (station 8) that is readily accessible during pancreatoduodenectomy (PD) to determine if increased miRNA levels correlate with postresection recurrence. Station 8 lymph nodes overlying the common hepatic artery collected during PD were assayed for miRNA-10b, miRNA-30c, miRNA-21, and miRNA-155 and cytokeratin-19 (CK19), an epithelial cell marker, using quantitative PCR. Expression was correlated with disease recurrence, recurrence-free survival (RFS), and overall survival (OS). Station 8 lymph nodes from 37 patients (30 periampullary carcinomas (PCs), 2 chronic pancreatitis, 5 other cancers) exhibited increased miRNA-10b levels in 14/30 PCs, and in 10 of these 14 patients, cancer recurred during the study period (2012–2015). High miRNA-10b was also associated with shorter RFS (42.5 vs. 92.4 weeks, p < 0.05) but not OS, whereas miRNA-30c, miRNA-21, and miRNA-155 levels and CK19 mRNA levels in station 8 nodes were variable and did not correlate with RFS or OS. We conclude that elevated miRNA-10b levels in station 8 lymph nodes could be utilized to assess risk for early disease progression in patients with periampullary tumors.

Total Serum Bilirubin within 3 Months of Hepatoportoenterostomy Predicts Short-Term Outcomes in Biliary Atresia

To prospectively assess the value of serum total bilirubin (TB) within 3 months of hepatoportoenterostomy (HPE) in infants with biliary atresia as a biomarker predictive of clinical sequelae of liver disease in the first 2 years of life. Infants with biliary atresia undergoing HPE between June 2004 and January 2011 were enrolled in a prospective, multicenter study. Complications were monitored until 2 years of age or the earliest of liver transplantation (LT), death, or study withdrawal. TB below 2 mg/dL (34.2 μM) at any time in the first 3 months (TB <2.0, all others TB ≥ 2) after HPE was examined as a biomarker, using Kaplan-Meier survival and logistic regression. Fifty percent (68/137) of infants had TB < 2.0 in the first 3 months after HPE. Transplant-free survival at 2 years was significantly higher in the TB < 2.0 group vs TB ≥ 2 (86% vs 20%, P < .0001). Infants with TB ≥ 2 had diminished weight gain (P < .0001), greater probability of developing ascites (OR 6.4, 95% CI 2.9-14.1, P < .0001), hypoalbuminemia (OR 7.6, 95% CI 3.2-17.7, P < .0001), coagulopathy (OR 10.8, 95% CI 3.1-38.2, P = .0002), LT (OR 12.4, 95% CI 5.3-28.7, P < .0001), or LT or death (OR 16.8, 95% CI 7.2-39.2, P < .0001). Infants whose TB does not fall below 2.0 mg/dL within 3 months of HPE were at high risk for early disease progression, suggesting they should be considered for LT in a timely fashion. Interventions increasing the likelihood of achieving TB <2.0 mg/dL within 3 months of HPE may enhance early outcomes. ClinicalTrials.gov: NCT00061828 and NCT00294684.

Retrospective analysis of second-line chemotherapy outcomes with paclitaxel or docetaxel in correlation with STMN1 polymorphism in advanced non-small cell lung cancer patients.

Second-line chemotherapy of advanced non-small cell lung cancer (NSCLC) with docetaxel or pemetrexed allows to achieve objective response rate only in 5-10 % of patients. Recent studies have shown that single nucleotide polymorphisms (SNPs) in genes encoding proteins which regulate dynamics of microtubules may be considered as predictive factors of response to taxane-based chemotherapy. STMN1 gene encodes stathmin 1, which plays role in cell division by regulation of microtubules depolarisation, and this process may be associated with taxanes' effectiveness. Using HRM-PCR technique, we evaluated the -2166C>T SNP of STMN1 gene in DNA from peripheral blood leucocytes of 54 advanced NSCLC patients treated in second-line monotherapy with docetaxel or paclitaxel. Patients with TT genotype of STMN1 gene demonstrated significantly longer progression-free survival (PFS) and the lower risk of early disease progression after second-line treatment compared to patients with other STMN1 genotypes (median PFS: 7 and 2 months; p = 0.0154; HR = 0.371; 95 % CI 0.184-0.743). Early disease progression during second-line chemotherapy was significantly more frequently observed in patients with CC genotype of STMN1 in contrast to patients with presence of T allele (median PFS: 2 and 4 months; p = 0.0385; HR = 1.776; 95 % CI 0.905-3.445). Only selected NSCLC patients could benefit from second-line chemotherapy. Therefore, investigations of novel predictive molecular factors for proper qualification of patients to second-line taxane-based chemotherapy are justified. Studied SNP of STMN1 gene may have potential predictive role in such therapy.